Mike: Hello, I'm Mike Clarke, podcast editor for the Cochrane Library. The Cochrane Gynaecology and Fertility Group has prepared more than 220 reviews and, in September 2022, a team from Germany, The Netherlands and New Zealand updated one of these, looking at the use of a drug called letrozole for subfertile women with anovulatory polycystic ovary syndrome. Lead author, Sebastian Franik from the University of Münster in Germany describes the latest findings in this podcast.

Sebastian: Polycystic ovary syndrome, or PCOS for short, is the most common cause of infrequent, or absent, periods worldwide, affecting about one woman in 10 and often leading to subfertility. Various drugs have been tested to help with this, with clomiphene citrate proving to be the most successful for several decades. However, in 2002, a new class of drugs called aromatase inhibitors were introduced for ovulation induction. Many clinical trials have reported that one of these, letrozole, might be at least as effective as clomiphene citrate but there have been fluctuating results. Therefore, we've been maintaining this Cochrane Review for more than 10 years to evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS, updating it every few years to bring in new information.
For each version of the review, we search for published and unpublished randomized trials in which an aromatase inhibitor was used alone or in conjunction with other medical therapies for ovulation induction in anovulatory women with PCOS. We've added five trials as part of this update and removed six others because of concerns about their validity. This leaves us with 41 studies, that had recruited more than 6500 subfertile women with PCOS.
Our primary outcomes were live birth rate, which was reported in 14 studies, and ovarian hyperstimulation syndrome rate, for which we could use data from 17 studies.
In total, 23 studies compared letrozole to clomiphene citrate with or without additional treatment and 11 of these reported on live birth rate. When we combined their results in a meta-analysis, it suggested that the odds of having a live baby were increased by 70% among women using letrozole rather than clomiphene citrate. Furthermore, there was high-quality evidence that ovarian hyperstimulation syndrome occurred with similar frequency with letrozole or clomiphene citrate. We were able to use data from 23 studies to investigate the proportion of women who became pregnant and found a 70% increase with letrozole. Where data were available on unintended side effects, there was no evidence to distinguish between letrozole and clomiphene citrate on miscarriage rate or multiple pregnancies.
We also compared letrozole against laparoscopic ovarian drilling in women with clomiphene resistance and PCOS. There was low-quality evidence that live birth rates were similar, but there was insufficient data to show evidence of a difference between the therapies on ovarian hyperstimulation syndrome. There was also not enough data to show whether or not the dose of letrozole made a difference to the main outcomes.
To sum up, our updated results suggest that subfertile women with PCOS treated with letrozole have better pregnancy and live birth outcomes than women treated with clomiphene, while the rates of ovarian hyperstimulation syndrome are similar. However, unanswered questions remain, including uncertainty about the dosage effects of aromatase inhibitors, which need to be tackled in studies comparing different drugs and doses and testing whether the use of multiple drugs is beneficial.

Mike: If you would like to explore the findings of this substantive update in more detail, just go online to Cochrane Library dot com and search 'aromatase inhibitors and PCOS'. That's also where you'll find further updates of the review, as new evidence becomes available and the current uncertainties are tackled.